CCAR2/DBC1 and Hsp60 Positively Regulate Expression of Survivin in Neuroblastoma Cells.

Wootae Kim,Ja-Eun Kim,Jaewook Ryu

doi:10.3390/ijms20010131

Wootae Kim, Ja-Eun Kim + Show 1 more

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https://doi.org/10.3390/ijms20010131

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Abstract

CCAR2 (cell cycle and apoptosis regulator 2) controls a variety of cellular functions; however, its main function is to regulate cell survival and cell death in response to genotoxic and metabolic stresses. Recently, we reported that CCAR2 protects cells from apoptosis following mitochondrial stress, possibly by co-operating with Hsp60. However, it is not clear how CCAR2 and Hsp60 control cell survival and death. Here, we found that depleting CCAR2 and Hsp60 downregulated expression of survivin, a member of the inhibitor of apoptosis (IAP) family. Survivin expression in neuroblastoma tissues and human cancer cell lines correlated positively with expression of CCAR2 and Hsp60. Furthermore, high expression of CCAR2, Hsp60, and survivin was associated with poor survival of neuroblastoma patients. In summary, both CCAR2 and Hsp60 are required for expression of survivin, and both promote cancer cell survival, at least in part, by maintaining survivin expression. Therefore, CCAR2, Hsp60, and survivin are candidate tumor biomarkers and prognostic markers in neuroblastomas.

Highlights

Cell cycle and apoptosis regulator 2 (CCAR2), formerly known as deleted in breast cancer 1 (DBC1), is an emerging key regulator of multiple cellular functions
The expression of survivin decreased in Hsp60-depleted cells, the interaction between CCAR2 and survivin still occurred in the absence of Hsp60 (Figure 1C, lane 5 vs. lane 6), indicating that CCAR2 is a core protein involved in sequestration of survivin
Q(EC,F-R) TPhMe (KFo) cdaakta(sEe)tsanwdeSreEQsuCb--RgProMup(Fed) daactcaosredtsinwgetroe neuroblastoma stage. sub-grouped according to neuroblastoma stage. We show that both CCAR2 and Hsp60 are required for maintenance of survivin expression

Summary

Introduction

Cell cycle and apoptosis regulator 2 (CCAR2), formerly known as deleted in breast cancer 1 (DBC1), is an emerging key regulator of multiple cellular functions. Other well-known functions of CCAR2 include regulation of cell death and survival. In the absence of exogenous insults, CCAR2 might act as either a promoter or suppressor of cell survival. CCAR2 knockout mouse embryonic fibroblasts (MEFs) show faster proliferation and colony formation than wild-type MEFs. By contrast, CCAR2-deficient cancer cells grow slowly, suggesting its role as a promoter for tumor cell survival [12,13]. The role of CCAR2 in cell death and survival may depend on the context, in terms of cell type and stimulus type

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